NK cells are innate lymphoid cells that play important roles in tumor eradication and viral clearance. We previously found that deletion or inhibition of the histone methyltransferase Ezh2 (enhancer of zeste homolog 2) in hematopoietic stem and progenitor cells (HSPCs) from both mice and humans enhanced the commitment and cytotoxicity of NK cells to tumor cells. This study tested the hypothesis that inhibiting Ezh2, especially in NK lineage cells, could also affect NK cell development and function. We crossed Ezh2^fl/fl mice with Ncr1^iCre mice to delete the Ezh2 gene in immature NK cells and downstream progeny. Ezh2 deficiency increased the total number of NK cells and promoted NK cell terminal differentiation, as the percentages of the most mature CD27^–CD11b⁺ subsets were increased. The NK cell cytotoxicity against tumor cells in vitro was enhanced, with increased degranulation and IFN-γ production. In addition, during the process of human NK cells differentiating from HSPCs , inhibiting EZH2 catalytic activity at day 14 (when NK lineage commitment began) also resulted in increased proportions of mature NK cells and cytotoxicity. Furthermore, RNA-seq and CUT&RUN-qPCR assays showed that the effects of Ezh2 may be based on its direct modulation of the expression of the transcription factor Pbx1 (pre-B-cell leukemia transcription factor 1), which has been reported to promote NK cell development. In summary, we demonstrate that Ezh2 is a negative regulator of NK cell terminal maturation and function.

中文翻译：

---

组蛋白甲基转移酶 Ezh2 负调控 NK 细胞终末成熟和功能

NK 细胞是先天淋巴细胞，在肿瘤根除和病毒清除中起重要作用。我们之前发现，小鼠和人类的造血干细胞和祖细胞 (HSPC) 中组蛋白甲基转移酶 Ezh2（zeste 同源物 2 的增强子）的缺失或抑制增强了 NK 细胞对肿瘤细胞的承诺和细胞毒性。这项研究检验了抑制 Ezh2，尤其是在 NK 谱系细胞中，也可能影响 NK 细胞发育和功能的假设。我们将Ezh2 ^fl/fl小鼠与Ncr1 ^iCre小鼠^杂交以删除Ezh2未成熟 NK 细胞和下游后代中的基因。Ezh2 缺乏增加了 NK 细胞的总数并促进了 NK 细胞终末分化，作为最成熟的 CD27 ^– CD11b ⁺的百分比子集增加了。NK 细胞在体外对肿瘤细胞的细胞毒性增强，脱粒和 IFN-γ 产生增加。此外，在人类 NK 细胞从 HSPC 分化的过程中，在第 14 天（当 NK 谱系定型开始时）抑制 EZH2 催化活性也会导致成熟 NK 细胞的比例增加和细胞毒性。此外，RNA-seq 和 CUT&RUN-qPCR 分析表明，Ezh2 的作用可能基于其直接调节转录因子 Pbx1（前 B 细胞白血病转录因子 1）的表达，据报道该转录因子可促进 NK细胞发育。总之，我们证明 Ezh2 是 NK 细胞终末成熟和功能的负调节剂。